of basel



Patented] @et. 331 1922 innate certain states @ATENT cannon.

KARL MIIESCHEE, 01E BASEL, SWETZERLAND, ASSIGNQR T SUCIE'EY OF CHEMICAL INDUSTRY IN BASJLE, 0F BASEL, SWITZERLAND.

AMINOALCOHOL or rain QUINOLINE snnms AND rnocnss or MAKING seam.

Ho Drawing.

To all whom it may concern:

Be it known that ll, KARL'MIESCWR, a citizen of the Swiss Republic, andresident of Basel, Switzerland, have invented new and useful Aminoalcohols of the Quinoline Series and Processes of Making Same, of

which the following is a full, clear, and exact specification.

The present invention relates to the manufacture of aminoalcohols by starting from 2-phenylquinoline4-carboxylic acid its derivatives (as for instance Q-phenylt-cyanquinoline and substitution products as for instance Q-phenyl-6-ethoxyquinoline-4-car- CO H COqCzHs by halogenating the ketone in the alkyl Applicatipn filed July as, 1921.

Serial No. 488,161.

boxylic acid). The 2-phenylquinoline-4tcarboxylic acid can be tranformed into 2+ phenylquinolyl-t alkylketones, either by condensing its esters with esters-of fatty acids in presence of sodium ethylate to fatty acid esters of 2-phenyl-4L-quinoloyl and subjecting these latter to the ketone splitting 0% by means of acids or by decomposing the nitrile of 2 -phenylquinoline- 4c-carboxylic acid according to the method of Grignard.

The production of 2-phenylquinoline-4- methylketone is for instance shown by the following scheme:

\ Acids CO.CHa

group and by reacting with amines on the halogenketones. For instance the Q-phe- CH3 d NJMg nylquinolyl-t-n1ethylketone can be trans- 40 reduced to 2-phenylt-aminoethanol bases.

.30 and 88' parts of messes CEKOEMJHWH Analo ous' bodies have already been prepared y starting from the cinchoninic acid or from the quininic acid and their n1- triles. The use of 2-phenylquinoline4-car- 5 boxylic acid as parent material for the syntheses signifies anessential progress relatively to the previously known process, since the 2-phenylquinolinel-carboxylic acid is by itself already therapeutically active, not

10. only because it favors the elimination of uric acid but also because it has antipyretic and analgetic properties. On the contrary cinchoninic and quininic acids are without action, as it is well known. The 2-phel5 nylquinoline shows also relatively to the quinoline itself according to the investi a tions of Grethe and Tap einer (Deutsc es Archiv fiir-klinische Me izin 56, 189, 369,

(1896) a manilt'oldly enhanced action against paramecia. This favorable influence of the phenyl group in the quinoline is alsofound again completely in the new derivatives.

Emmples.

1'. Preparation of the 2- kenyl-tguimZog lacetic ethy ster.

parts: of v 2-phenylquinoline-4-carboxylester, 68 parts of sodiumethylate dry acetic ethylester are heated in 200parts of toluene for 24 hours on a water bath, the whole being dissolved. Then the solution is cooled down, the sodi- 11m saltof the pheii'yl uinolylacetic ester is 5 extracted. with water, t e resulting solution acidulated with sulfuric acid until it shows an acid reactioniwith Congo and the precipitating heavy oil is dissolved in ether. After drying and evaporation of the sol- 40 vent, there remains the 2-phenylquinoloyldaceticethyl ester in form of an oilwhich solidifies after a certaih'time may he brown solu tion is recrystallized from a little methylalcohol or intense-yellow salts capable of 2. Preparation of the fi-plapnylgwim'ly l-k methylktone I pfienylgudrwlo'ylcicetz'ceeter.

1 part of 2-phenyl-4-quinoloylacetice%yl ester is heated with 8 parts of sulfuric acid of 25 per cent on a water bath. There is formed a ketone sulfate, while carbonic acid is evolved. By treating with sodium carbonate and with ether the free ketone is separated and can be tion ofthe ether in form of an oil solidifying in presence of alcohol.

he 2-phenylquinolylemethylketone thus obtained is formed'by yellow crystals melting at 75 C. It is easily solublein benzene and in hot alcohol, diflicultly soluble in ether and in cold alcohol. Its hydrobromide constitutes yellow crystals melting at 240 C.

lsonitroeo/cetone.

- 49.4; parts of Q-phenylquinolyl-d-niethylketone are dissolved together with $3.4

' (a) from parts of amylnitrite in '120 parts of benzene and the mixture is poured into a solution of 4.1 parts of sodium in 10.0- lute alcohol while stirring.

let to stand for 1n a well closed ice-safe. The-sodium salt of the isonitrosoketone precipitates. dissolved in water; this solution is shaken It is obtained b evaporaparts ,of aloso- 4 alongtime for 2 hours on a water-bath;

' melting at 91 sition. It is insoluble in water,

parts of glacial acetic with benzene and acidulated with the calculated quantity of acetic acid, whereby the isonitrosoketone is precipitated. It crystallizes from alcohol in the form of yellowish crystals and melts at 182 C. with decompobenzene and carbon sulfide, diflicultly soluble in ether and soluble in acetone, boiling alcohol or Xylene.

(b) from Q-phenyZ--cyangrbinoline.

2-phenyl-4-cyanquinoline is prepared according to the German Patent Specification 288243 by distilling the amide of 2-phenylquinoline-4-carboxylic acid. Into a solution of 23 parts of phenylcyanquinoline in dry benzene is introduced, drop by drop, while cooling, methylmagnesium iodide prepared from 142 parts of methyliodide and 24.3 parts of after cooling there is added ice thereto, and it is acidulatedwith acetic acid. The separation is then effected and the solvent is evaporated,

By triturating the residue with alcohol, the

' phenylquinolyl methylketone separates in a crystalline state. (3) Preparation of 2-phenyZ-guin0ZyZ-4- bromornethylketone. I

The hydrobromide of 2-phenylquinolyl- 4'-brornomethylketone is obtained with an excellent yield by brominating the phenylquinolineketone in concentrated hydrobromic acid or in an organic solvent.

The 2-phenylquinolyl-4-acetic ester can also be brominated and the carbethoxyl group be split off in the same operation by heating the solution of hydrobromide.

(1). 16.4 parts of phenylquinolylmethylketone hydrobromide are dissolved .in 50 acid at 90 (1., there are added While stirring, 8 parts of bromine and 10 parts of glacial acetic acid, drop by drop. The 2-phenylquinolyl-4-bromomethylketone hydrobromide separates as intensely yellow colored crystals which are filtered ofi in the cold. It melts unsharply at about 225 C. with decomposition. The free base formsC bright-yellowish crystals (2). 185 parts of i2l-phenylquinolyl-4- methylketone are dissolved in 750 parts of hot concentrated hydrogen bromide of specific gravity of 1.48, and to the solution thus obtained there are added, dropby drop, 12 parts of bromine dissolved ofhydrog'en bromide at? 0 (1., while stirring. The hydrobromide of the bromoketone an ethereal solution oi into 50 parts,

filtration.

(4) Preparation of the aminoketoms.

The aminoketones are obtained advantageously by reaction of 1 mol. of a salt of 2- phenylquinolyl-4-halo enalkylketone with 3 mol. of a free amine. Tut the said aminoketones are not stable and are best isolated as hydrochloride or hydrobromide.

(a) To 13.5 parts of dimethylamine dis solved in 400 parts of benzene, are added by portions, while cooling with ice, 40.7 parts of ;:2-phenylquinolyl-4-bromomethylketone hydrobromide. After standing for 1 hour the dimethylamine hydrobromide is precipitated quantitatively. After filtration, the residue is washed with benzene and from the yellow solution the aminoketone is precipitated. with somewhat alcoholic hydroch lIpric acid than the calculated quantity.

he ethanone monohydroch oride separates as bright-yellow crystalclust. It crystallizes from absolute alcohol by addition of ether and melts at 208 C. with decomposition.

The corresponding monohydrobromide melts unsharply at about 206 C.

(b) 4.38 parts of diethylamine are dissolved in 70 parts of ether, and to the resulting solution are added 814 parts of bromoketone hydrobromide while cooling with ice. The product of reaction is isolated as .indicated under a. The 2-phenylquinolyl- 4-diethylaminoethanone monohydrobromidc is obtained by crystallization from alcohol 2-phenylquinolyl-l-dimethylaminoand ether in the form of bright-yellow felt- 5 Preparation of ammwzaomn.

The aminoalcohols with primary aminogroup can be prepared by reducing the .corresponding isonitrosoketone, whilst the N- sub'stituted aininoalcohols can be obtained easily by reduction of the corresponding of alkalies;

.aminoketones. The N-substituted free bases precipitate in an amorphous state from theaqueous solution of their salts on addition they are easily soluble in all solvents except in petroleum ether and in water; They cannot be preserved for a long time and become quickly brown in the air.- The bases give monoacid salts dimcultly-s'oluble in Water and biacid salts readily soluble in Water.

(a) 6.9 parts of 2-phenylquinolyli-isonitr'osoketone are dissolved in .6'0 parts of formic acid of er cent and to the resulting solution are ad ed, while stirring, 5.9. parts ofzinc dust. After the achievement of the reaction, the mass is diluted with water and the zinc is preci itated by means of hydro gene sulfide. he filtrate is concentrated and afterwards sodium acetate is added thereto in order to separate. a secondary product and the base not difiicultly soluble in water-is precipitated with a concentrated is extracted with quantit of hydrochloric acid solution of potassium carbonate. This base ether and isolated in'the form of hydrochloride. The 2-phenylchino-' lyl-4-aminoethanol dihydrochloride constitutes ellowish, nearly white or stals, readily so uble in water, which, wlien crystallized from alcohol, melt at C. to a dull mass which clears at about 190 (7.,

(h) 31 parts of 2 phenylquino1yl-4-di- I methylaminoethanone hydrobromide are suspended in a twentyfold quantity of, water and shaken withhydrogen after a, molecular and 25 partsof a co loidal platinum solution of 0.4 per cent have been added. When the calculated quantity of hydrogen is absorbed and the whole is dissolved, the platinum is precipitated and filtered ofi and the ethanolbase is liberated by a solution of sodium carbonate. It precipitates as a white amorphous mass. The latter is dissolved in ether. B addition-of the calculated quantity' of a coholic hydrochloric acid the dihydroch methylaminoethanolIprecipitates as a crystalline substance. constitutes a white feebly yellowish flowde'r easily soluble in water and hot alcohol, melting unsharply at about C. with decomposition.

and hot alcohol and 'apeutic properties loride of '2-phenyl-4qu1nolyl dineeeeoe (e) 10 parts ofg-phenylquinolyl-d-diethylas I e ochloride melts at about C. while becoming brown. It is yellowish. white, easily soluble in water and hot alcohol and diilicultly soluble in acetone.

(d) to parts of 2-phen'ylquinolyl-4- iperidoethanone hydrochloride are issolved in 50 parts of formic acid and to the resulting solution there are added progressively 1.2 parts of nine dust, while stirring. The reaction achieved, the m is supersaturated with alkali, the base solved in ether and precipitated therefrom by alcoholic hydroch oric acid.

The 2-phenylquinolyl-d-piperidoethanol dihydrochloride is a white, feebly, yellowish, crystalline powder, and melts at about 199 (3., when recrystallized from alcohol, whilst the corresponding monohydrochloride melts at about 162 C. The former is easil soluble in water, the latter more dificult y.

If the base is liberated from an aqueous solution of the salts with a solution of soat dium carbonate, it precipitatesinthe form of white flocks. When washed with water pressed on clay and dried over a mixture 0 lime and sodium hydroxide, the base softens at about 48 C. and melts at about 54- C. to By standing it becomes quickly brown and smells like piperidine.

What I claim is:

As new products, the aminoalcohols of p the 2-phenylquinoline series having their 95 aminoalcohol group in position 4 of the quinoline nucleus, which form yellowish White monoor diacid salts soluble in water having valuable therwe 11 witness whereof I have hereunto signed my name this 14th day of July, 1921, in the presence of the subscribing witness.

KARL mason. 1 

